L16: Calcium-Phosphate Homeostasis & Growth Hormone

Phosphate distribution in the body

84% bone

15% intracellular anion

1% muscle & ECF

Phosphate exist as

inorganic and organic forms in the body, bound to oxygen and measured in assays

Forms of inorganic phosphate

- diphosphate

- monophosphate

Functions of inorganic phosphate

acts as a buffer (eg. during acidosis)

Binding of inorganic phosphate

~10% bound to proteins

Somatotropin

growth hormone

Somatostatin (GHIH)

growth hormone inhibiting hormone, acts as a negative feedback mechanism to balance the amount of GH in the bloodstream

GHRH

growth hormone releasing hormone, stimulates the release of GH from the anterior pituitary

Insulin-like growth factor (IGF-1)

produced in the liver, responsible of for growth-promoting effects of GH

Acromegaly / Hypersomatotropism

abnormal growth of bones & tissues due to excessive secretion of GH, usually due to benign functional pituitary gland tumor

Gigantism

a condition produced by hypersecretion of growth hormone during the natural growth phase of an animal

Dwarfism

condition caused by insufficient growth hormone early in life

25% percent of cats in the UK suffering from diabetes mellitus have

a tumor in the anterior pituitary gland that secretes excess amount of growth hormone

What type of phosphate is typically measured in blood biochemical assays?

inorganic phosphate

Vitamin D effect on phosphate levels

enhances phosphate absorption from diet, increases P

PTH effect on phosphate levels

causes bone to release phosphate & kidneys to excrete more

There is a mild increase in phosphate young pups & kittens due to

rapid bone growth

Insulin effect on phosphate levels

drives phosphate into cells

Growth hormone effects on phosphate levels

affect phosphate handling by kidneys

Hyperphosphatemia from increased intake

- excessive dietary intake or phosphate enemas

- hypervitaminosis D

Hyperphosphatemia from physiologic reasons

high phosphate from bone development in young animals

Hyperphosphatemia from decreased excretion

- reduced renal excretion

- hypoparathyroidism (low PTH)

Hyperphosphatemia from shifting

- hemolysis (shifting from ICF - ECF)

Hyperphosphatemia from hyperparathyroidism

21% of cats show elevated phosphate

Hypophosphatemia from decreased intake

- starvation, anorexia, malabsorption

- V/D

- "refeeding syndrome" in cats

Hypophosphatemia from increased losses

- renal losses: hyperparathyroidism (high PTH), pseudohyperparathyroidism (high PTHrP)

- osmotic diuresis

Hypophosphatemia from shifting ICF

insulin therapy = rapid phosphate uptake into cells

Hypophosphatemia from defective mobilization

post-parturient states (milk fever, eclampsia)

Explain the pathogenesis:

- Secondary renal hyperparathyroidism

- Increased P

chronic kidney disease leads to decreased renal phosphate excretion & hyperphosphatemia

Explain the pathogenesis:

- Healthy, 4-month-old puppy

- Increased P

growing animals have higher phosphate due to increased bone turnover & growth hormone

Explain the pathogenesis:

- Phosphate enema

- Increased P

absorption of phosphate salts leads to hyperphosphatemia

Explain the pathogenesis:

- Hemolyzed sample

- Increased P

intracellular phosphate from lysed RBCs is released into serum & falsely leads to increased P levels

Explain the pathogenesis:

- Milk fever/Eclampsia

- Decreased P

hypocalcemia from increased calcium demand (lactation) leads to PTH release, enhances renal phosphate excretion

Elevated PTH in the presence of hypercalcemia strongly suggets

primary hyperparathyroidism (due to parathyroid adenoma)

Increased PTHrP in the presence of hypercalcemia suggests

pseudo-hyperparathyroidism (increased PTHrP) from Humoral Hypercalcemia of Malignancy (HHM)

Possible causes of vitamin D intoxication

ingestion of cholecalciferol-containing rodenticides, excessive vitamin D supplementation, certain plants

What causes DM in feline acromegaly?

a tumor secreting growth hormone

What is growth hormone release controlled by?

GH-releasing hormone (GHRH)

GH levels are highest during

adolescence, decline with age

GH is released in a pulsatile fashion with superimposed peaks caused by

- hypoglycemia

- ghrelin

- exercise/stress/trauma

- sleep

- progesterone

Growth hormone - IGF Axis two mechanisms

1. direct metabolic effects via GH-receptors on target cells

2. indirect effects via stimulation of IGF-1

During LOW energy situations (hypoglycemia/low insulin), what happens to hepatic GH receptors?

downregulated by insulin

LOW energy situations switches metabolism to

free fatty acid utilization while reserving blood glucose for the glc-dependent tissues (brain)

In diabetic animals, the GH-IGF axis works

directly only

During HIGH energy situations, what happens to hepatic GH receptors?

upregulated by insulin

What is the anabolic GH-IGF axis effect on cartilage & bones?

- bone length increases during adolescence

- osteocyte & osteoblast stimulation in adult bones - bone thickness & density

What is the anabolic GH-IGF axis effect on muscles?

development & strength

Seppi, a German Shepherd puppy, suffers from an inherited mutation of the LHX3 gene, which leads to underdevelopment of its anterior pituitary gland. The condition is called juvenile onset panhypopituitarism. Which endocrine systems can be affected?

thyroid, gonads, adrenals

Juvenile onset panhypopituitarism is common in what species?

german shepherds

GH-IGF axis dysfunction deficiency is seen as

juvenile onset panhypopituitarism combined with hypothyroidism (TSH), hypogonadism (FSH/LH), hypoadrenocorticism (ACTH)

Physical exam findings of GH-IGF axis deficiency

insufficient growth (dwarfism), retained puppy coat, bilateral alopecia, delayed dentition, small sexual organs, infertility

Diagnosis of GH-IGF axis deficiency

hormone assays: IGF-1, GH, thyroids, cortisol, genetic testing

Treatment of GH-IGF axis deficiency

hormone supplementation throughout life

GH-IGF axis dysfunction excess before puberty is seen as

giantism due to excess epiphyseal growth

Acromegaly effects on protein & carbohydrate metabolism

- hypertrophy of muscles inc. cardiac & organs

- increased bone & cartilage thickness

- increased gluconeogenesis & insulin resistance = secondary DM

Acromegaly signs

joint problems, increased body weight, facial broadening, paw enlargement, increased interdental spaces from teeth shifting

What percentage of diabetic cats may suffer from acromegaly?

25-30%

Diagnosis of acromegaly

hormone assays (GH, IGF-1)

secondary DM (glucose, fructosamine)

CT/MRI

Treatment of acromegaly

stereotactic radiation therapy

surgery

somatostatin analogs

insulin